EP3710592B1 - Procédé microbiologique pour la préparation d'amides - Google Patents

Procédé microbiologique pour la préparation d'amides Download PDF

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Publication number
EP3710592B1
EP3710592B1 EP18796959.7A EP18796959A EP3710592B1 EP 3710592 B1 EP3710592 B1 EP 3710592B1 EP 18796959 A EP18796959 A EP 18796959A EP 3710592 B1 EP3710592 B1 EP 3710592B1
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reaction
process according
microbiological process
samples
added
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German (de)
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EP3710592A1 (fr
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Stefano TONIOLO
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Columbia Srl
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Columbia Srl
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/88—Lyases (4.)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y402/00—Carbon-oxygen lyases (4.2)
    • C12Y402/01—Hydro-lyases (4.2.1)
    • C12Y402/01084—Nitrile hydratase (4.2.1.84)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales

Definitions

  • the present invention relates to a process for the preparation of amides and, more particularly, to a process for the preparation of amides from the corresponding nitriles by enzymatic hydrolysis with nitrile hydratase enzyme from a bacterial strain of Rhodococcus biphenylivorans species.
  • Nitriles are important precursors for the synthesis of amides and carboxylic acids, widely used as pharmaceutical active ingredients or as advanced intermediates for their synthesis.
  • the chemical hydrolysis can be also not suitable for obtaining amides because the hydrolysis procedure must be stopped to prevent the conversion to acid.
  • enzymatic hydrolysis may be used.
  • Several enzymatic processes for the conversion of nitriles to amides by using bacterial strains which produce nitrile hydratase enzyme also referred to as NHase are known in the literature.
  • nitrile hydratase enzyme produced by the strain of Rhodococcus biphenylivorans named "Palladio 22" and deposited on 12/04/2016 in the Collection of Microorganisms BCCM (Belgian Coordinated Collections of Microorganisms)-LMG with deposit number LMG P-29520 in compliance with the requirements of the Budapest Treaty is capable to convert a wide variety of nitriles to the corresponding amides with good chemoselectivity, regioselectivity and stereoselectivity.
  • BCCM Belgian Coordinated Collections of Microorganisms
  • Rhodococcus biphenylivorans The strain of Rhodococcus biphenylivorans named "Palladio 22" has been already described to be useful in the production of acrylamide in the International patent application WO2017199200 filed by the present Applicant and published on November 23, 2017 .
  • object of the present invention is a microbiological process for the preparation of amides of formula R(R')(R")C-CONH 2 (I) comprising the reaction of a nitrile of formula R(R')(R")C-CN (II) with the nitrile hydratase enzyme produced by the bacterial strain Rhodococcus biphenylivorans named "Palladio 22" deposited in the Collection of Microorganisms BCCM-LMG with deposit number LMG P-29520,
  • C 1 -C 6 alkyl is used as commonly understood by a skilled in the art and refers to a chemical entity having a carbon skeleton or a main carbon chain comprising a number from 1 to 6 (including all the single integers within the range as well as the integers 1 and 6) of carbon atoms.
  • Each C 1 -C 6 alkyl can be linear or branched.
  • branched is used as commonly understood by a skilled in the art and refers to a chemical entity having a skeleton or a main chain which splits into more than one contiguous chain.
  • the portions of the skeleton or of the main chain which split into more than one direction can be linear, cyclic or any combinations thereof.
  • Non limiting examples of a branched alkyl are tert-butyl, isobutyl and isopropyl.
  • linear is used as commonly understood by a skilled in the art and refers to a chemical entity having a skeleton or a main chain which does not split into more than one contiguous chain.
  • Non limiting examples of linear alkyls are methyl, ethyl, n-propyl and n-butyl.
  • C 3 -C 6 cycloalkyl is used as commonly understood by a skilled in the art and refers to a compound or to a chemical entity in which at least a portion of the carbon skeleton or main chain of the chemical entity is bound to form a ring of atoms which are linked together.
  • the atoms do not need to be all directly linked each other, but rather they need to be directly linked to at least other two atoms.
  • Non limiting examples of C 3 -C 6 cycloalkyl include cyclopropane, cyclobutane, cyclopentane and cyclohexane.
  • C 3 -C 6 heteroalkyl is to be understood to refer then to a compound or to a chemical entity in which at least a portion of the skeleton or of the main atom chain of the chemical entity, which includes at least a heteroatom, is bound to form a ring of atoms which are linked together.
  • the atoms do not need to be all directly linked each other, but rather they need to be directly linked to at least other two atoms.
  • aryl and “heteroaryl” are used as commonly understood by a skilled in the art and refer to a compound or to a chemical entity in which at least a portion of the skeleton or of the main atom chain of the chemical entity is bound to form an aromatic ring.
  • C 1 -C 6 alkyl includes, for example and without limitations, methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, n-hexyl, i-hexyl, 1,2-dimethylpropyl, 2-ethylpropyl, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1,2-triethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, sec-hexyl, t-hexyl.
  • Non limiting examples of C 2 -C 6 alkenyl include vinyl, allyl, isopropenyl, 1-propen-2-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 2-buten-1-yl, 2-buten-2-yl.
  • Non limiting examples of C 3 -C 6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • Non limiting examples of aryl include phenyl (Ph) and naphthyl.
  • heterocycle groups include pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, phthalimide and succinimide.
  • heteroaryl groups include pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl.
  • the process object of the present invention applies to the preparation of amides of formula I wherein at least one among R, R', R" and R′′′ is or contains a functional group sensitive to hydrolysis or solvolysis under acid, basic or neutral catalysis and environment selected among an additional nitrile group, an ester group, an amido group, a haloalkyl group, an ammonium salt.
  • the high selectivity of the process object of the present invention advantageously allows to carry out the conversion of the nitrile group only, without altering other functional groups present in the starting compound of formula II.
  • This feature is peculiar to the process object of the present invention and it represents its more advantageous and innovative characteristic.
  • nitriles which can be used in the microbiological process object of the present invention are provided, without any limitative purpose. All the nitriles in the table are known compounds and most of them are used as intermediates in processes for the preparation of pharmaceutical active ingredients (API).
  • API pharmaceutical active ingredients
  • the enzyme can be used in purified form or as component of the bacterial biomass.
  • the enzyme can be also used in immobilized form according to conventional techniques, for example onto a solid-type substrate.
  • the enzyme is used in the form of a biomass as a paste having then a dry residue at 105°C within a range from 20 to 45%, preferably from 25 to 40%.
  • the enzyme can be also used in the form of a dried/lyophilized biomass having a dry residue at 105°C from 90 to 100%, preferably from 95 to 99%.
  • the amount of enzyme can vary depending on the biocatalyst activity.
  • the amount can range from 2 g to 8 g, preferably from 3 to 6 g, to obtain 1 Kg ADM at 100%.
  • the lyophilized biomass instead, about from 0.5 to 2 g, preferably from 0.75 g to 1.5 g, are used to obtain the same quantity.
  • the process object of the present invention is carried out in aqueous solution, preferably in the presence of an organic co-solvent.
  • the function of the co-solvent is mainly that to enhance the dissolution of the nitrile and/or amide. Therefore, the type of co-solvent and its amount will depend on the characteristics of the nitrile to be hydrolyzed and of the amide to be obtained and they could be changed based on the knowledge of the skilled in the art.
  • the co-solvent will be selected among methanol, ethanol, tetrahydrofuran, methyl-tetrahydrofuran, 1,4-dioxane, toluene, t.BuOMe.
  • Methanol and toluene are particularly preferred.
  • the amount of co-solvent is generally between 2% and 20% v/v, preferably between 5% and 15%, still more preferably about 10%.
  • the preferred pH range within which the process object of the present invention is carried out is from 6.0 to 9.0. More preferably the pH range is from 6.5 to 7.5.
  • the desired pH value is obtained by using a suitable buffer in the reaction mixture.
  • a suitable buffer in the reaction mixture.
  • the use of phosphate buffer is particularly preferred.
  • reaction temperature can vary depending on the substrate to hydrolyze to promote the conversion rate. In general the temperature could range from 10 to 45°C, preferably from 15 to 30°C.
  • the substrate final concentration 50 mM
  • a suspension of the enzyme (NHase 4 mg) in buffer (9 mL).
  • sonication or heating were applied, if needed.
  • the reactions were followed in time (1 mL samples) by different analytical methods. Every sample was quenched with MeOH, filtered and analyzed.
  • the HPLC chromatogram was comparable to a synthetized sample of tert -butyl 4-carbamoylpiperidin-1-carboxylate.
  • NHase (16 mg) was grinded in a mortar and added to demineralized water (40 mL) in a 100 mL Erlenmeyer. The suspension was mixed by vortex and adiponitrile (224 ⁇ L, 0.5 mmol) was added to this suspension dissolved in toluene (400 ⁇ L). The reaction was stirred by orbital stirring at 25°C and 250 rpm. The reaction was followed by GC-MS. Samples (1 mL) were analyzed in time. Samples were mixed with MeOH (2 mL), filtered, evaporated under vacuum and dissolved in MeOH. 5-Cyanopentanamide (92 mg) was isolated in 37% yield.

Claims (10)

  1. Procédé microbiologique pour la préparation d'amides de formule

            R(R')(R")C-CONH2     (I)

    comprenant la réaction d'un nitrile de formule

            R(R')(R")C-CN     (II)

    avec l'enzyme nitrile hydratase produite par la souche bactérienne Rhodococcus biphenylivorans appelée « Paladio 22 » déposée dans la collection de microorganismes BCCM-LMG avec le numéro de dépôt LMG P-29520,
    dans lesquelles
    au moins l'un des groupes R, R' et R" est différent de l'atome d'hydrogène ;
    R, R' et R", groupes identiques ou différents les uns des autres, sont indépendamment choisis parmi un atome d'hydrogène, les groupes C1-C6 alkyle, C1-C6 alcoxy, C1-C6 alcoxycarbonyle, C2-C6 alcényle, C3-C6 cycloalkyle contenant éventuellement un groupe =O, R‴CO-, hétérocycle avec 3 à 6 atomes parmi lesquels au moins l'un représente un atome N ou O, arylsulfonyle, C1-C6 alkylsulfonyle, aryle, arylaminocarbonyle et C1-C6 alkylaminocarbonyle ;
    R'" représente un groupe C1-C6 alkyle, aryle, amino, hydrazino ;
    chaque groupe R, R', R" et R‴, lorsqu'il est différent d'un atome d'hydrogène, étant éventuellement substitué par un ou plusieurs substituants choisis parmi un atome d'halogène, les groupes nitrile, amino, C1-C6 alkylamino, hydroxy, C1-C6 alcoxy, aryle ;
    à condition que le composé de formule 1 ne soit pas l'acrylamide.
  2. Procédé microbiologique selon la revendication 1 pour la préparation d'amides de formule 1 dans laquelle au moins l'un des groupes R, R', R" et R'" représente ou contient un groupe fonctionnel sensible à l'hydrolyse ou à la solvolyse dans une catalyse ou un environnement acide, basique ou neutre choisi parmi un groupe nitrile supplémentaire, un groupe ester, un groupe amide, un groupe halogénoalkyle, un sel d'ammonium.
  3. Procédé microbiologique selon la revendication 1 ou 2, ladite enzyme étant utilisée sous la forme d'une biomasse sous forme de pâte présentant ensuite un résidu sec à 105°C compris dans la plage allant de 20 à 45 %, de préférence de 25 à 40 %.
  4. Procédé microbiologique selon la revendication 1 ou 2, ladite enzyme étant utilisée sous la forme d'une biomasse sèche/lyophilisée présentant un résidu sec à 105°C allant de 90 à 100 %, de préférence de 95 à 99 %.
  5. Procédé microbiologique selon la revendication 3 ou 4, ladite biomasse étant immobilisée sur un substrat de type solide.
  6. Procédé microbiologique selon l'une quelconque des revendications précédentes effectué en solution aqueuse, de préférence en présence d'un co-solvant organique.
  7. Procédé microbiologique selon la revendication 6, ledit co-solvant étant choisi parmi le méthanol, l'éthanol, le tétrahydrofurane, le méthyl-tétrahydrofurane, le 1,4-dioxaeo, le toluène, le t.BuOMe, de préférence parmi le méthanol et le toluène.
  8. Procédé microbiologique selon la revendication 6, la quantité de co-solvant étant comprise entre 2 % et 20 % en v/v, de préférence entre 5 % et 15 %, encore plus préférablement d'environ 10%.
  9. Procédé microbiologique selon l'une quelconque des revendications précédentes, ladite réaction étant effectuée à un pH allant de 6,0 à 9,0, de préférence de 6,5 à 7,5.
  10. Procédé microbiologique selon l'une quelconque des revendications précédentes, ladite réaction étant effectuée à une température allant de 10 à 45°C, de préférence de 15 à 30°C.
EP18796959.7A 2017-11-14 2018-11-09 Procédé microbiologique pour la préparation d'amides Active EP3710592B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT201700129625 2017-11-14
PCT/EP2018/080711 WO2019096677A1 (fr) 2017-11-14 2018-11-09 Procédé microbiologique pour la préparation d'amides

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EP3710592A1 EP3710592A1 (fr) 2020-09-23
EP3710592B1 true EP3710592B1 (fr) 2022-08-31

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EP (1) EP3710592B1 (fr)
JP (1) JP7149337B2 (fr)
CN (1) CN111757940B (fr)
WO (1) WO2019096677A1 (fr)

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JP2023523585A (ja) * 2020-04-24 2023-06-06 ファルマツェル、ゲーエムベーハー 複素環式α－アミノアミドの位置選択的酸化
CN114671784A (zh) * 2021-12-16 2022-06-28 青岛科技大学 一种由丙烯腈制备牛磺酸的方法

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JP4307837B2 (ja) * 2001-01-09 2009-08-05 ロンザ ア−ゲ− アミド類を生成するための微生物学的方法
JP2002325587A (ja) * 2001-03-02 2002-11-12 Daicel Chem Ind Ltd ニトリルヒドラターゼ、およびアミドの製造方法
FR2835531B1 (fr) * 2002-02-06 2004-12-03 Snf Sa Procede pour la fabrication d'amides en presence d'une nitrile hydratase d'origine microbiologique et nouveau microorganisme
TW200634151A (en) * 2004-12-09 2006-10-01 Asahi Chemical Ind Transformant expressing nitrile hydratase
ITUA20163572A1 (it) * 2016-05-18 2017-11-18 Columbia S R L Metodo biotecnologico per la produzione di acrilammide e relativo nuovo ceppo batterico

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Publication number Publication date
US11261468B2 (en) 2022-03-01
WO2019096677A1 (fr) 2019-05-23
CN111757940B (zh) 2023-11-07
JP2021502821A (ja) 2021-02-04
CN111757940A (zh) 2020-10-09
JP7149337B2 (ja) 2022-10-06
EP3710592A1 (fr) 2020-09-23
US20200248216A1 (en) 2020-08-06

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